The main objective of this project is to identify improved therapeutic options for patients with CML. Imatinib is standard therapy for CML, but nearly 20% of patients never achieve complete cytogenetic remission, and most have residual disease by polymerase chain reaction, and 10-15% of those who achieve remission eventually progress. More potent tyrosine kinase inhibitors (TKI) such as dasatinib and nilotinib have significant clinical activity after imatinib failure. The first aim is to determine whether dasatinib or nilotinib may improve the molecular response, and event-free and progression-free survival of patients with newly diagnosed chronic phase CML. Patients will be treated in one of two parallel studies with the primary objective to improve the molecular response rate at 12 months. The second aim is to investigate whether immunotherapy, in the form of PRI vaccine, can improve molecular responses of patients with minimal residual disease on imatinib therapy. Because Interferon may improve the expression of proteinase 3 from which PRI is derived, patients with this phenotype will be randomized to receive PRI and imatinib, with or without interferon. The primary objective is to improve the molecular response with PRI vaccine. Based on data originated through this grant suggesting activation of JAK2 in Bcr-Abl-positive cells, the third aim is to investigate whether JAK2 inhibition may have clinical activity in CML patients refractory to TKI. We will conduct a phase 2 trial of INCB18424, a JAK2 inhibitor, in patients who failed at least 2 TKI. The long-term plan is to use this agent in combination with TKI. The fourth aim deals with the problem of patients with blast phase, a group with dismal outcome with available therapy. Dasatinib induces high response rates but most patients eventually relapse. Increased methylation is associated with progression in CML. We will thus treat patients with blast phase CML with decitabine, a hypomethylating agent, and dasatinib to determine whether this combination may improve the rate and durability of responses in blast phase CML. Overall, this project may lead to improved long-term outcome for patients with all phases ofthe disease and get us closer to complete eradication of CML.